Validation of machine learning models to detect amyloid pathologies across institutions.

Semi-quantitative scoring schemes like the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) are the most commonly used method in Alzheimer's disease (AD) neuropathology practice. Computational approaches based on machine learning have recently generated quantitative scores for whole slide images (WSIs) that are highly correlated with human derived semi-quantitative scores, such as those of CERAD, for Alzheimer's disease pathology. However, the robustness of such models have yet to be tested in different cohorts. To validate previously published machine learning algorithms using convolutional neural networks (CNNs) and determine if pathological heterogeneity may alter algorithm derived measures, 40 cases from the Goizueta Emory Alzheimer's Disease Center brain bank displaying an array of pathological diagnoses (including AD with and without Lewy body disease (LBD), and / or TDP-43-positive inclusions) and levels of Aβ pathologies were evaluated. Furthermore, to provide deeper phenotyping, amyloid burden in gray matter vs whole tissue were compared, and quantitative CNN scores for both correlated significantly to CERAD-like scores. Quantitative scores also show clear stratification based on AD pathologies with or without additional diagnoses (including LBD and TDP-43 inclusions) vs cases with no significant neurodegeneration (control cases) as well as NIA Reagan scoring criteria. Specifically, the concomitant diagnosis group of AD + TDP-43 showed significantly greater CNN-score for cored plaques than the AD group. Finally, we report that whole tissue computational scores correlate better with CERAD-like categories than focusing on computational scores from a field of view with densest pathology, which is the standard of practice in neuropathological assessment per CERAD guidelines. Together these findings validate and expand CNN models to be robust to cohort variations and provide additional proof-of-concept for future studies to incorporate machine learning algorithms into neuropathological practice

Switching to second-line antiretroviral therapy in resource-limited settings: comparison of programmes with and without viral load monitoring.

In high-income countries, viral load is routinely measured to detect failure of antiretroviral therapy (ART) and guide switching to second-line ART. Viral load monitoring is not generally available in resource-limited settings. We examined switching from nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line regimens to protease inhibitor-based regimens in Africa, South America and Asia

Orally active antischistosomal early leads identified from the open access malaria box.

BACKGROUND: Worldwide hundreds of millions of schistosomiasis patients rely on treatment with a single drug, praziquantel. Therapeutic limitations and the threat of praziquantel resistance underline the need to discover and develop next generation drugs. METHODOLOGY: We studied the antischistosomal properties of the Medicines for Malaria Venture (MMV) malaria box containing 200 diverse drug-like and 200 probe-like compounds with confirmed in vitro activity against Plasmodium falciparum. Compounds were tested against schistosomula and adult Schistosoma mansoni in vitro. Based on in vitro performance, available pharmacokinetic profiles and toxicity data, selected compounds were investigated in vivo. PRINCIPAL FINDINGS: Promising antischistosomal activity (IC50: 1.4-9.5 µM) was observed for 34 compounds against schistosomula. Three compounds presented IC50 values between 0.8 and 1.3 µM against adult S. mansoni. Two promising early leads were identified, namely a N,N'-diarylurea and a 2,3-dianilinoquinoxaline. Treatment of S. mansoni infected mice with a single oral 400 mg/kg dose of these drugs resulted in significant worm burden reductions of 52.5% and 40.8%, respectively. CONCLUSIONS/SIGNIFICANCE: The two candidates identified by investigating the MMV malaria box are characterized by good pharmacokinetic profiles, low cytotoxic potential and easy chemistry and therefore offer an excellent starting point for antischistosomal drug discovery and development

Frequency-tunable metamaterials using broadside-coupled split ring resonators

We present frequency tunable metamaterial designs at terahertz (THz) frequencies using broadside-coupled split ring resonator (BC-SRR) arrays. Frequency tuning, arising from changes in near field coupling, is obtained by in-plane horizontal or vertical displacements of the two SRR layers. For electrical excitation, the resonance frequency continuously redshifts as a function of displacement. The maximum frequency shift occurs for displacement of half a unit cell, with vertical displacement resulting in a shift of 663 GHz (51% of f0) and horizontal displacement yielding a shift of 270 GHz (20% of f0). We also discuss the significant differences in tuning that arise for electrical excitation in comparison to magnetic excitation of BC-SRRs

Scalable Similarity Search for Molecular Descriptors

Similarity search over chemical compound databases is a fundamental task in the discovery and design of novel drug-like molecules. Such databases often encode molecules as non-negative integer vectors, called molecular descriptors, which represent rich information on various molecular properties. While there exist efficient indexing structures for searching databases of binary vectors, solutions for more general integer vectors are in their infancy. In this paper we present a time- and space- efficient index for the problem that we call the succinct intervals-splitting tree algorithm for molecular descriptors (SITAd). Our approach extends efficient methods for binary-vector databases, and uses ideas from succinct data structures. Our experiments, on a large database of over 40 million compounds, show SITAd significantly outperforms alternative approaches in practice.Comment: To be appeared in the Proceedings of SISAP'1

Praziquantel: its use in control of schistosomiasis in sub-Saharan Africa and current research needs

Treatment with praziquantel (PZQ) has become virtually the sole basis of schistosomiasis control in sub-Saharan Africa and elsewhere, and the drug is reviewed here in the context of the increasing rate that it is being used for this purpose. Attention is drawn to our relative lack of knowledge about the mechanisms of action of PZQ at the molecular level, the need for more work to be done on schistosome isolates that have been collected recently from endemic areas rather than those maintained in laboratory conditions for long periods, and our reliance for experimental work mainly on Schistosoma mansoni, little work having been done on S. haematobium. There is no evidence that resistance to PZQ has been induced in African schistosomes as a result of its large-scale use on that continent to date, but there is also no assurance that PZQ and/or schistosomes are in any way unique and that resistant organisms will not be selected as a result of widespread drug usage. The failure of PZQ to produce complete cures in populations given a routine treatment should therefore solicit considerable concern. With few alternatives to PZQ currently available and/or on the horizon, methods to monitor drug-susceptibility in African schistosomes need to be devised and used to help ensure that this drug remains effective for as long a time as possibl

Nanohertz Frequency Determination for the Gravity Probe B HF SQUID Signal

In this paper, we present a method to measure the frequency and the frequency change rate of a digital signal. This method consists of three consecutive algorithms: frequency interpolation, phase differencing, and a third algorithm specifically designed and tested by the authors. The succession of these three algorithms allowed a 5 parts in 10^10 resolution in frequency determination. The algorithm developed by the authors can be applied to a sampled scalar signal such that a model linking the harmonics of its main frequency to the underlying physical phenomenon is available. This method was developed in the framework of the Gravity Probe B (GP-B) mission. It was applied to the High Frequency (HF) component of GP-B's Superconducting QUantum Interference Device (SQUID) signal, whose main frequency fz is close to the spin frequency of the gyroscopes used in the experiment. A 30 nHz resolution in signal frequency and a 0.1 pHz/sec resolution in its decay rate were achieved out of a succession of 1.86 second-long stretches of signal sampled at 2200 Hz. This paper describes the underlying theory of the frequency measurement method as well as its application to GP-B's HF science signal.Comment: The following article has been submitted to Review of Scientific Instruments. After it is published, it will be found at (http://rsi.aip.org/

Efficacy and Safety of Mefloquine, Artesunate, Mefloquine-Artesunate, and Praziquantel against Schistosoma haematobium: Randomized, Exploratory Open-Label Trial

Background. Morbidity control of schistosomiasis relies on a single drug, praziquantel. The antimalarial drug mefloquine possesses interesting antischistosomal properties, yet no clinical studies have been performed. Methods. We conducted a randomized, exploratory open-label trial to assess the efficacy and safety of mefloquine (25 mg/kg), artesunate (3 doses of 4 mg/kg), mefloquine-artesunate (3 doses of 100 mg artesunate plus 250 mg mefloquine), and praziquantel (40 mg/kg) against Schistosoma haematobium. The effects on Schistosoma mansoni, malaria parasitemia, soil-transmitted helminths, and intestinal protozoa were also determined. Results. A total of 83 S. haematobium-infected schoolchildren were included in the study. Cure rates of mefloquine, artesunate, mefloquine-artesunate, and praziquantel against S. haematobium at day 26 after treatment were 21%, 25%, 61%, and 88%, respectively. Both mefloquine-artesunate and praziquantel resulted in egg reduction rates >95%. Significantly lower egg reduction rates were seen in the artesunate (85%) and mefloquine groups (74%). In children coinfected with S. mansoni, praziquantel and mefloquine-artesunate, but not mefloquine and artesunate alone, resulted in high cure rates and egg reduction rates. Mefloquine, artesunate, and mefloquine-artesunate completely cured infections due to Plasmodium falciparum. No effects were found against soil-transmitted helminths and intestinal protozoa. Abdominal pain was the most frequent adverse event, with a higher incidence among children treated with mefloquine (89%), mefloquine-artesunate (83%), and artesunate (60%) than among children treated with praziquantel (46%). Conclusions. The high efficacy of mefloquine-artesunate against S. haematobium warrants further investigation. Individuals coinfected with Plasmodium and Schistosoma who were treated with a mefloquine-artesunate combination against malaria might have a dual benefit: clearance of malaria parasitemia and reduction of schistosomiasisrelated morbidity. Clinical trials registration. Current Controlled Trials identifier: ISRCTN0649876